(a) Field of the Invention
The present invention relates to biodegradable and bioabsorbable BAB-block copolymers that exhibit reverse thermal gellation properties upon exposure to elevated temperatures, such as upon exposure to body temperature just prior to or upon administration. The disclosed polymers are advantageously used, for example, in the parenteral administration of drugs.
(b) Description of the Related Art
Biodegradable block copolymers exhibiting reverse thermal gellation are disclosed in U.S. Pat. Nos. 6,201,072; 6,117,949; and 6,004,573 to Rathi et al. and 5,702,717 to Cha et al., each of which is incorporated by reference herein. These polymer compositions exist as a liquid solution at low temperatures, then reversibly form gels at physiologically relevant temperatures, and provide good drug release characteristics. These compositions include biodegradable ABA- or BAB-type block copolymers having a weight average molecular weight of between about 2000 and 4990, and include about 51 to 83% by weight of an hydrophobic A polymer block comprising a biodegradable polyester and about 17 to 49% by weight of a hydrophilic B polymer block comprised of polyethylene glycol. The U.S. Pat. Nos. 7,018,645 and 7,135,190 to Piao et al., disclose mixtures of triblock copolymers exhibiting similar reverse thermal gellation properties.
The Rathi patents disclose BAB-block copolymers having reverse thermal gellation properties. According to the '949 Patent, BAB triblock copolymers were synthesized using the same PEG B-block at either end (Mw=550) but varying the poly(lactide) and/or poly(glycolide) content. The PEG and PLGA were coupled to each other via ester, urethane, or a combination of ester and urethane links. The prior BAB-block copolymers described in the Rathi patents had a weight average molecular weight Mw ranging from 2000 to 4990. The following table lists characteristics of the BAB triblock copolymers disclosed in the Rathi patents:
BAB Block Copolymers with ReverseThermal Gellation PropertiesGPC Weight AverageWeight %PLA:PGAReverse ThermalMolecular WeightA-Blocks(mole ratio)Gellation41407078:22Yes42707278:22Yes45807378:22Yes45107372:28Yes
All of the PEG-PLGA-PEG triblock copolymers listed in the above table possessed reverse thermal gelation properties. The sol/gel transition temperatures for the above triblock polymers were 36, 34, 30 and 26° C. respectively. While the Rathi patents demonstrated good drug release characteristics for ABA-triblock copolymers having a weight average molecular weight Mw in the range of 2000-4990 Daltons, the Rathi patents did not characterize the release characteristics of the disclosed BAB-triblock copolymers. Additionally, release characteristics were not investigated with respect to hydrophilic compounds. It has been found that the release characteristics of prior triblock copolymer compositions for hydrophilic active agents are not suitable for many controlled release applications.